1-substituted biguanides

ABSTRACT

Novel 1-aryl and aralkyl biguanide compounds have been prepared. The compounds of this invention possess useful gastric antisecretory and spasmolytic properties. Compounds of this type which also display anti-hypertensive and CNS depressant properties are also disclosed.

United States Patent 1 Diamond et al.

14 1 Sept. 18, 1973 l-SUBSTITUTED BIGUANIDES [75] Inventors: JuliusDiamond, Lafayette Hill;

George H. Douglas, Paoli; Bernard J. Burns, Philadelphia, all of Pa.

[73] Assignee: William H. Rorer, lnc., Ft.

Washington, Pa.

[22] Filed: Apr. 27, 1972 [21] Appl. No.: 248,298

Related US. Application Data [62] Division of Ser. No. 89,005, Nov. 12,1970,

abandoned.

[52] US. Cl 260/565, 260/453 A, 260/454,

260/518 R, 260/564 B, 260/471 A, 260/556 AR, 260/501.l4, 260/295.55,260/404.5,

[51] Int. Cl. C07c 129/08 [58] Field of Search 260/565 [56] ReferencesCited OTHER PUBLICATIONS Chemical Abstracts, Vol. 55, Column l5966(d)(1961) Primary ExaminerLeon Zitver Assistant ExaminerGerald A. SchwartzAttorney-James A. Nicholson [57] ABSTRACT 9 Claims, No Drawings 1l-SUBSTITUTED BIGUANIDES CROSS REFERENCE TO RELATED APPLICATIONS This isa division, of application Ser. No. 89,005, filed Nov. 12, 1970, nowabandoned.

SUMMARY OF THE INVENTION This invention describes new l-substitutedbiguanide compounds and processes for their preparation. This inventionfurther provides valuable pharmaceutical preparations which containl-substituted biguanide compounds as active gastric anti-secretory andspasmolytic agents. A method for the treatment of gastrointestinaldisorders and diseases is also described. The-compounds of thisinvention also possess an effective degree of antihypertensive and'CNSdepressant.

BACKGROUND OF THE INVENTION The pharmaceutical compositions which havebeen used as gastric antisecretory and spasmolytic agents have been suchas atropine, homatropine, propantheline bromide, dicyclominehydrochloride and" other compounds which are structurally dissimilar: tothe biguanides of this invention. Due to the anticholinergic propertiesof these compoundsthey are known to produce undesirable side effectssuch as mydriasis, xerostomia, cyclopegia'and other unwantedseffects.

There have been a number of l-aryl and-aralkylbiguanides described inthe literature. They have been proposed for use as antidiabetics,anorexigenic orantimalarial agents. .l. H. Burn and .l. R; Vane,however, in The Brit J. Pharmacol. (1948), 3:346-9 testedl-(pchlorophenyl)biguanide and l-(p-meth'oxyphenynbiguanide for theirability to reduce gastric secretion. Their findings determined thatlittle or no reduction of gastric secretion was associated with thesecompounds. Contrary to this belief:

We have unexpectedly found that the l-substituted biguanides of thisinvention are valuable pharmacologic agents which possess useful gastricantisecretory and spasmolytic properties.

We have also found that the compounds of this invention aresubstantially free of the anticholinergic side-effects which accompanygastric antisecretory and spasmolytic agents.

We have further found that the compounds of this invention have a loworder of toxicity.

We have still further found a simple and effective method for treatinggastrointestinal disorders and diseases, such as duodenal and pepticulcers.

We have found that the l-substituted biguanides of this invention alsohave an effective degree of antihypertensive and CNS depressant.

DESCRIPTION AND PREFERRED EMBODIMENT This invention describes a class ofnovel chemical R R R R & R may be the same or different and arehydrogen, loweralkyl,

nitro,

amino,

haloloweralkoxy,

haloloweralkyl,

hydroxy,

cyano, thiocyanato,

carboxy, carbalkoxy,

diloweralkylsulfonamido,

phenoxy,

acyloxy,

halophenoxy,

phenyl'or halophenyl;

R R R & R may also be halo and loweralkoxy; R may also be halo and loweralkoxy provided R R R & R are not all hydrogen at the same time;

and their non-toxic acid addition salts.

The more preferred compounds for a method of treating gastrointestinaldisorders and diseases and for use in gastrointestinal therapeuticcompositions embrace those compounds of structural formula II,

where: R and R are hydrogen,

halo,

haloloweralkyl or alkoxy;

R is hydrogen,

haloloweralkyl,

hydroxy,

nitro, or

halo provided both R, and R are not both hydrogen at the same time.

The most :preferred compounds for a method of treating gastrointestinaldisorders and diseases and for use in gastro-intestinal compositionsembrace those compounds of structural formula II, where:

R R and R are hydrogen,

chloro,

bromo,

trifluoromethyl, provided R is not chloro when both R and R arehydrogen.

ln the descriptive portions of this invention, the following definitionsapply:

The term lower alkyl" refers to an alkyl hydrocarbon group containingfrom 1 to about 8 carbon atoms which may be straight chained orbranched.

The "acyl" radical may be any organic radical derived from an organicacid by its removal of the hydroxyl group such as acetyl, propionyl,benzoyl, etc.

The lower alkoxy radical signifies an alkoxy group containing from 1 toabout 8 carbon atoms which can be straight chained or branched.

The compounds of structural formula I are also useful in the treatmentof hypertensive and CNS depressant disorders. The more preferredcompounds used in a method of treating hypertensive disorders are thosedescribed by figure II where R, is hydrogen. The most preferredcompounds are those described by figure ll where: R and R are chloro,

bromo or trifluoromethyl.

This invention further describes new chemical compounds which aregenerically described by the structural formula as shown in FIG. I.

where:

n is -1;

R is hydrogen or lower alkyl;

R R R R & R may be the same or different and are:

haloloweralkyl,

hydroxy, cyanato,

carboxy, carbalkoxy,

diloweralkylsulfonamido,

phenoxy, halophenoxy,

acyloxy,

haloloweralkoxy or phenyl, halophenyl;

R R R & R may also be bromo,

chloro,

nitro,

amino,

dialkylamino or cyano; when R & R are substituted then R may also behydrogen,

bromo,

chloro,

iodo,

nitro or cyano;

R and R may be hydrogen; and R and R may be hydrogen, when n is arefewer than 4 hydrogens present.

The more preferred compounds of this invention embrace those compoundsof structural formula I where: n is 0.

1 provided there The most preferred compounds of this invention embracethose compounds of structural formula ll where n is 0 and R and R are 5iodo,

chloro,

bromo,

fluoro or nitro; and R is hydrogen,

halo,

nitro, or

trifluoromethyl.

It is well known in the pharmacological arts that nontoxic acid additionsalts of pharmacologically active amine compounds do not differ inactivities from their free base. The salts merely provide a convenientsolubility factor.

The amines of this invention may be readily converted to their non-toxicacid addition salts by customary methods in the art. The non-toxic saltsof this invention are those salts the acid component of which ispharmacologically acceptable in the intended dosages; such salts wouldinclude those prepared from inorganic acids, organic acids, higher fattyacids, high molecular weight acids, etc. and includes such as:

hydrochloric acid, succinic acid hydrobromic acid, glycolic acid,sulfuric acid, lactic acid, nitric acid, salicylic acid,

benzoic acid,

phosphoric acid,

nicotinic acid,

methane sulfonic acid,

it will further be appreciated by one skilled in the art that thefollowing radicals may be employed in the practice of this invention:

where:

n is also 2;

R is loweralkenyl, cycloloweralkyl, haloloweralkyl, arloweralkyl oraryl;

R R R R & R is loweralkenyl, aminoloweralkyl, alkylaminoloweralkyl,hydroxyloweralkyl, mercapto, loweralkylthio, loweralkylsulfinyl,loweralkylsulfonyl, sulfonamido, loweralkoxyloweralkyl,mercaptoloweralkyl, loweralkylmercaptoloweralkyl,arloweralkylmercaptoloweralkyl, arloweralkyl, arloweralkenyl, halobenzylanilino, loweralkoxyphenyl, biphenylyl, phenoxy, benzyloxy,

a polyfluoro substituted group such as trifluoromethylsulfonyl,

trifluoroacetyl,

trifluoroacetoxy,

trifluorocarbomethoxy,

di-(trifluoromethylamino)sulfonyl,

di-(trifluoromethylamino)carbonyl, or

B,fi-difluorovinyl. I

The products of this invention can contain an asymetric carbon atom whenn=l. For this reason they may be obtained as racemic mixtures or asdextro and levorotatory isomers. These may be separated by any of thevarious methods of resolution. A method that may be employed iscombining the racemic compound with an optically active compound, forexample, by salt formation. Two products are then obtained. If theinstant biguanides are added to an optically active acid, such as or()-tartaric acid, then the salts produced possess different propertiesand different solubilities and can be separated by fractionalcrystallization. When the salts have been separated by repeatedcrystallization, the acid is split off and the pure dor 1- biguanidecompound is obtained. It is to be understood that these optical isomersare embraced within the extent of this invention.

Representative compounds of this invention which are particularly usefulare as follows:

l-( p-trifluoromethylphenyl)biguanide l-(p-trifluoromethoxyphenyl)biguanide l-( p-dimethylsulfamylphenyl)biguanide l-( p-trifluoromethylbenzyl )biguanide l2,6-dichlorophenyl)biguanide l-(2,6-dibromophenyl)biguanidel-(2,4,6-trichlorophenyl)biguanide l-( 2 ,6-dichlorobenzyl )biguanidel-(2,4,6-trichlorobenzyl)biguanide l-( 2 ,6-dichloro-4-hydroxyphenyl)biguanide l-( 2 ,6-dichloro-a-methylbenzyl)biguanide l-( 3,5-ditrifluoromethylphenyl)biguanide 1-( 3 ,4,5-trimethoxyphenyl)biguanide 1-(2,4,6-trimethoxyphenyl)biguanidel-(3,5-dichloro-4-methoxyphenyl)biguanide-(2,3,4,6,-tetrafluorophenyl)biguanide(2,3,4,5-tetrafluorophenyl)biguanide(2,6-dibromo-4-trifluoromethylphenyl)biguanide(2,4,-tribromophenyl)biguanide (2,6-dibromo-4-chlorophenyl)biguanide(2,6-dichloro-4-bromophenyl)biguanide(2,6-dichloro-4-trifluoromethylphenyl)biguanide(2,4-dichloro-6-thiocyanatophenyl)biguanide(2,6-dibromo-4-fluorophenyl)biguanide2,6-dichloro-4-thiocyanatophenyl)biguanide2,6-dichloro-4-fluorophenyl)biguanide 2,6-dibromo-4-iodophenyl)biguanide2,6-dichlor-4-nitrophenyl )biguanide2,4-dichloro-6-nitrophenyl)biguanide2,6-dinitro-4-chlorophenyl)biguanide 2,6-dibromo 4-nitrophenyl)biguanide 2,6,4'-trichloro-4-biphenyl)biguanide l-(2,6-dichloro-4-phenoxyphenyl)biguanide l-(2,6,4'-trichloro-4-phenoxyphenyl)biguanide l-( 2,6-dibromo-4-(4-chlorophenoxy)phenyl)biguanide l-(2,6-dibromo-4-phenoxyphenyl)biguanide l-( 2,6-dibromo-4'-chloro-4-biphenyl)biguanide l-(2,4-dichlorophenyl)biguanidel-(2,3-dichlorophenyl)biguanide 1 l l l l l 1 1 l l l l l l l l 6l-(2,5-dichlorophenyl)biguanide l-(2,4-dibromophenyl)biguanide Thecompounds of this invention may be prepared by the following generalprocedures:

Condensation of cyanoguanide and an aryl or aralkylamine in the presenceof an equimolar amount of a mineral acid results in the correspondingaryl or aralkylbiguanide.

The following reaction equation illustrates this synthesis:

ve, and HX is a mineral acid.

The reaction is preferably carried out on the aryl or aralkylamine salteither in a polar medium or neat and using increased temperatures. Thesalt used may be any acid addition amine salt but preferably the salt ofa mineral acid. The polar medium may be aqueous, partially aqueous or anon-aqueous solution. It is convenient to choose a solvent that willreflux at the desired reaction temperature. The more preferred solventsare water or alcohol but other solvents may be used such as DMSO,diethyleneglycol, ethyleneglycol, tetrahydrofuran, dimethylformamide,etc. The reaction should also be carried out at a temperature which ishigh enough so that condensation takes place readily, but not sufficientto decompose the biguanide formed. The reaction temperature can varyfrom room temperature to about 250 C although it is preferable to runthe reaction at temperatures from about 50 to C. The biguanide saltwhich is formed can be converted to the free base with a metal hydroxideor alkoxide solution. The isolation of the desired biguanide can becarried out by any method known in the art.

Appropriately desired end products having various R R R R and Rsubstituents can be prepared at various stages of synthesis usingsuitable reactions in order to convert one group to another. Thus, forexample, using conventional methods, a halogen group can be treatedunder Rosenmund Von Brown conditions to the nitrile compound which inturn can be hydrolyzed to a carboxy. A nitro can be reduced to an aminowhich can be alkylated to the dialkylamino substituent. A hydroxycompound can be prepared by demethylation of a methoxy substituent. ASandmeyer type reaction can be carried out on an amino compound tointroduce a chloro, bromo, xanthate, hydroxyl or alkoxyl group. Thexanthate can then lead to the mercapto byhydrolyl-(4-trifluoromethylphenyl)biguanide l-(2,6-dibromo-4-trifluoromethylphenyl)biguanide l-(4-bromophenyl)biguanidel-(2,4,6-tribromophenyl)biguanide l-(4-fluorophenyl)biguanidel-(2,6-dibromo-4-fluorophenyl) biguanide l-(4-chlorophenyl)biguanidel-(2,6-dibromo-4-chlorophenyl) biguanide l-(2,o-dichlorophenyl)biguanidel-(2,6-dichloro-4-bromophenyl) biguanide I 4-iodophenyl )biguanidel-(2,6-dibromo-4-iodophenyl) biguanide l-( 4-nitrophenyl )biguanide l-(2,6-dibromo-4-nitrophenyl) biguanide l-( 2,6-dibromo-4 '-chloro-4-biphenyl)biguanide l-(2,6-dibromo-4- phenoxyphenyl) biguanide l-[ 2,6dibromo-4-(4 chlorophenoxy) phenyl lbiguanide l-(2,4-dichloro-6-bromophenyl) biguanide l-(4'-chloro-4-biphenyl)biguanideI -(4-phcnoxyphenyl)biguanide l-[ 4-(4-chlorophenoxy)phenyl biguanidel-(2,4-dichlorophenyl)biguanide In an analogous manner, chlorination,nitration and thiocyanation can also be carried out to obtaincorresponding products. Other reactions known in the art may also beemployed.

The starting materials of this invention are either known compounds ortheir method of preparation is described.

We have found that the compounds of this invention have a useful degreeof gastric anti-secretory activity and are effective in reducing thevolume and the acidity of the gastric fluid in humans and mammals.Further, these compounds produce a considerable spasmolytic action onthe gastrointestinal musculature, i.e., they reduce the peristalticaction of the gastrointestinal musculature which is manifested by adelay in gastric emptying time.

Until now, the known gastric anti-secretory and gas tro-intestinalspasmolytic compounds have included such agents as atropine,homatropine, propantheline, dicyclomine, etc. These compounds, however,cause accompanying undesirable anti-cholinergic properties such asmydriasis, xerostomia, cyclopegia, etc. We have found that the l-aryland aralkylbiguanides of this invention are particularly useful asgastric antisecretory agents because they are essentially devoid ofthese unwanted effects. It should further be noted that these compoundsare alsocharacterized by their low acute oral toxicity.

In particular the l-aryl and aralkyl-biguanides as herein described areuseful in the treatment of such gastrointestinal disorders and diseasesas duodenal ulcer and peptic ulcer.

The instant compounds may be used alone or in combination with otherknown antacids such as aluminum 8 hydroxide, magnesium hydroxide,magnesium trisilicate, aluminum glycinate, calcium carbonate and thelike.

For all these purposes, the biguanides of this invention can be normallyadministered orally or parenterally. Orally they may be administered astablets,agueous or oily suspension, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. The termparenteral as used herein, includes subcutaneous injection, intravenous,intramuscular or intrasternal injection or infusion techniques.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apharmaceutically elegant and palatable preparation. Tablets whichcontain the active 1 aryl and aralkylbiguanide ingredient in admixturewith non-toxic pharmaceutically acceptable excipients are suitable forthe manufacture of tablets. These excipients may be, for example, inertdiluents, for example, calcium carbonate, sodium carbonate, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example, maize starch or alginic acid; binding agents, forexample, starch, gelatin or acacia; and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with an oilmedium, for example, arachis oil, liquid paraffin or olive oil.

Aqueous solutions containing the active l-aryl and aralkyl biguanidesform a further embodiment of this invention. Excipients suitable foraqueous suspensions, may be employed if desired. These excipients aresuspending agents, for example, sodium carboxymethyl- 'cellulose,methyl-cellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidine, gum tragacanth and gun acacia; dispersing orwetting agents may be a naturally occuring phosphatide, for example,lecithin; or condensation products or an alkylene oxide with fattyacids, for example, polyoxyethylene stearate; or condensation productsof ethylene oxide with longchain aliphatic alcohols, for example,heptadecaethyleneoxy-cetanol; or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol, for example,polyoxyethylene sorbitol monooleate; or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example, polyoxyethylene sorbitan monooleate. The saidaqueous suspensions may also contain one or more preservatives, forexample, ethyl, or npropyl, p-hydroxy benzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose.

Oily suspensions may be formulated by suspending the active ingredientin a vaegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil, such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example, sweetening, flavoring andcoloring agents, may also be present.

The compounds of this invention may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example, olive oilor arachis oils, or a mineral oil, for example, liquid paraffin ormixtures of these. Suitable emulsifying agents may be naturallyoccurringgums, for example, gum acacia or gum tragacanth, naturally-occurringphosphatides, for example, soya bean lecithin, andesters or partialesters derived from fatty acids and hexitol anhydrides, for example,sorbitan mono-oleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated'with sweetening agents, forexample, glycerol, sorbitol or sucrose.

Such formulations may also contain a demulcent, a preservative andflavoring and coloring agents. The pharmaceutical compositions may be inthe form of a sterile injectable preparation, for example, as a sterileinjectable aqueous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or-wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterallyacceptable diluent or solvent,for example, as an aqueous solution buffered to a pH of 4.0 to 7.0 andmade isotonic with sodium chloride.

Further, these compounds may be tableted or otherwise formulated so thatfor every 100 parts by weight of the composition, there are presentbetween and 95 parts by weight of the active ingredient. The dosage unitform will generally contain between about 1 mg. and about 500 mg of theactive ingredients of this invention. The preferred unit dose is betweenabout mg and about 100 mg.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective in thetreatment of gastrointestinal disease conditions or symptoms, such asduodenal and peptic ulcer, and in the alleviation of hypertensivedisorders. In general, the daily dose can be between about 0.5 mg/kg and70 mg/kg (preferably in the range of 2-25 mg/kg/day), bearing in mind,of course, that in selecting the appropriate dosage in any specificcase, consideration must be given to the patients weight, generalhealth, age, and other factors which may influence response to the drug.

Various tests in animals have been carried out to show the ability ofthe compounds of this invention to exhibit reactions that can becorrelated with activity in humans. These tests involve such factors asthe effect of the l-aryl and aralkylbiguanides on gastric secretion,their spasmolytic effect, their mydriatic effect and determinationoftheir toxicity. It has been found that the compounds of this inventionwhen tested in the above variety of situations show a marked activity.

One such test is the gastric secretion test. This test is carried out asfollows: Shay rats are fasted for 48 hours, and water is given ad lib.The rats are selected at random and separated into groups of 10. Theanimals are treated intraduodenally (l.D.) with the test compound or thevehicle immediately subsequent to the ligation of the stomach at thepyloric sphincter. The animals are sacrificed with chloroform at 4 hourspostdrug administration, the stomach is removed and its contents areassayed for volume, pH and total acids.

A second gastric secretion test is carried out on the dog. This isoutlined in the Handbook of Physiology, Section 6: Alimentary Canal,Volume ll: Secretion. American Physiology Society, Washington, D.C.,1967.

It has been found that the compounds of this invention when subjected tothe above gastric secretion tests display marked ability to decreasegastric volume and gastric acidity. These tests are known to correlatewell with gastric activity in humans and are standard tests used todetermine anti-secretory properties.

To determine the anti-ulcer effectiveness the following test isemployed: Male Wiston rats (l30-l50 grams) are fasted for 24 hours, thengiven reserpine at 5 mg/kg i,p. Twenty-four hours later, the stomachsare removed and examined for ulceration. Ulcers are graded on a 0-4scale and the number of ulcers is recorded. Pretreatment with thebiguanide compounds produces a decrease in ulcer grade and the number ofulcers compared to the control reserpine-treated rats.

Determination of anti-spasmolytic properties can be carried out by theprocedure as outlined by D. A. Brodie and S. K. Kundrats in theirarticle entitled Effect of Drugs on Gastric Emptying in Rats," Fed.Proc. 24:714 (l965).

Mydriasis is detected by the procedure of R. A. Turner, ScreeningMethods in Pharmacology, Academic Press, New York, and London, pp.174-5, 1965. Acute toxicity is calculated according to the standardLitchfield-Wilcoxon procedure.

In view of the results of these tests, the pharmacological data clearlyindicates that the l-aryl and aralkylbiguanides of this invention can beconsidered to be active gastric anti-secretory and anti-spasmolyticagents which are substantially free of anti-cholinergic side effects andhaving a low toxicity.

Tests in animals have been carried out to show the ability of compoundsof this invention to inhibit reactions that can be correlated withhypertensive effects in humans. One such test is outlined by..lacques deChamplain, Lawrence R. Krahoff and Julius Axelrod in CirculationResearch XXlll:479 (i968 This testing method is known to correlate wellwith hypertensive activity in humans and is a standard test used todetermine anti-hypertensive properties. in view of the results of thistest, the l-aryl and aralkyl biguanides of this invention can beconsidered to be active antihypertensive agents.

To determine the CNS depressant effectiveness of the compound of FormulaI, the suppression of spontaneous motor activity is evaluated in normalmice (18-22 g) and immature rats (-l00 g) by a modification of the Dewmethod: Dews, Brit. J. Pharmacol: 8, 46 (1953). Results of this testindicate that a relative increase in depressant activity is evident.

The following are detailed examples which show the preparation of thecompounds of this invention. They are to be construed as illustrationsof said compounds and not as limitations thereof.

Example 1 1-( p-Trifluoromethoxyphenyl)biguanide dihydrochloride Astirred mixture of 6.3 g. (0.0296 mole) of p-aminophenyltrifluoromethylether hydrochloride and 2.49 g. (0.0296 mole) of cyanoguanidine isimmersed in a 210 C. oil bath for minutes. The resulting amber glasslikereaction product is dissolved in 100 ml of water, alkalized with 40percent sodium hydroxide solution, and extracted with 250 ml of ether.The ether layer is backwashed twice with 10 ml of water, dried oversodium carbonate, filtered, and the ether solution made strongly acidicwith a saturated ethereal hydrochloric acid solution. The precipitate iscollected on a filter, washed twice with 50 ml of anhydrous ether, anddried at C/l25 mm. Recrystallization from a mixture of isopropanol andcyclohexane (121) gives l-(p-trifluoromethoxyphenyl) biguanidedihydrochloride (m.p. 209-21l C).

Example 2 l-(p-Trifluoromethylbenzyl)biguanide dihydrochloride A stirredmixture of 6.9 g (0.035 mole) of p-trifluoromethylbenzylaminehydrochloride and 2.9 g (0.035 mole) of cyanoguanidine is immersed in a180 C oil bath for 1 hour. The melt is cooled and dissolved in ml of hotwater. The solution is cooled in an ice bath, made alkaline with percentsodium hydroxide solution, and extracted with 150 ml of ether. The etherlayer is dried over potassium carbonate, filtered and the ether solutionmade strongly acidic with a saturated ethereal hydrochloric acidsolution. The precipitate is washed twice with 25 ml of anhydrous etherand recrystallized from a mixture of ethanol and heptane (3:5) to obtainl-(p-trifluoromethylbenzyl)biguanide (m.p. 223225 C.)

Example 3 l-(a-Methyl-p-trifiuoromethylbenzyl )biguanide dihydrochlorideA stirred mixture of 15.5 g (0.0687 mole) ofa-methyl-p-trifluoromethylbenzylamine hydrochloride and 6.35 g (0.0756mole) of cyanoguanidine is immersed in a 190 C oil bath for 10 minutes.The melt is cooled to room temperature, dissolved in 100 ml of water,made alkaline with 40 percent sodium hydroxide solution and extractedtwice with 200 ml of ether. The combined ether extracts are dried overpotassium carbonate, filtered, and the ether solution made stronglyacidic with a saturated ethereal hydrochloric acid ether solution. Theprecipitate is collected on a filter, washed twice with 50 ml. ofanhydrous ether, and dried at 40 C/l25 mm. for 5 hours. Thedihydrochloride is dissolved in 50 ml. of water, made strongly alkalinewith 40 percent sodium hydroxide solution, and extracted twice with 100ml of ether. The combined ether extracts are dried over potassiumcarbonate, filtered, and the ether solution made strongly acidic with asaturated ethereal hydrochloric acid solution. The precipitate iscollected on a filter, washed twice with 50 ml of anhydrous ether, anddried at 40 C/l25 mm. to obtainl-(a-methyl-ptrifiuoromethylbenzyl)biguanide dihydrochloride.

Example 4 l-( 2,6-Dichlorophenyl)biguanide A stirred mixture of 300 g(1.85 mole) of 2,6- dichloroaniline, 155 g. (1.85 mole) ofcyanoguanidine and 712 ml of 2.6 N hydrochloric acid (L mole) is treatedat 60 C for several hours. The reaction mixture is then cooled,alkylated with 40 percent sodium hydroxide and extracted with lzlether-ethanol. The extract is washed with a saturated saline solutionand dried over sodium sulfate. The solvent is evaporated and replacedwith benzene which on concentrating results in the crude product. Theresidue is dissolved in ml of hot methanol and 200 ml of water is added.The precipitate is removed, washed with water and dried. Thehydrochloride salt is then made in alcohol to obtainl-(2,6-dichlorophenyl)biguanide hydrochloride (m.p. 236 C).

Example 5 l-( p-N ,N-Dimethylsulfamylphenyl)biguanide To 11 g (0.055mole) of p-N,N-dimethylsulfamylaniline is added 17.68 ml (0.055 mole of3.1N hydrochloric acid. This is heated on a steam bath with 15 ml ofisopropanol and 4.62 g (0.055 mole) of cyanoguanidine. The reactionmixture is heated for 18 hours. The alcohol is evaporated off anddiluted with 250 ml of 7.4 percent hydrochloric acid. The mixture isfiltered, cooled and made alkaline with 10 percent sodium hydroxide. Theprecipitate is filtered, triturated with 100 ml of boiling isopropanoland filtered to get l-(p-N,N- dimethylsulfamylphenyl)biguanide (m.p.l90-l90.5 C).

Example 6 l-(2,4,6-Trichlorophenyl)biguanide hydrochloride To 20 g (0.1mole) of 2,4,6-trichloroaniline and 10 g (0.1 mole) of cyanoguanidine in10 ml (0.1 mole) of concentrated hydrochloric acid is added ml ofnbutanol. The reaction mixture is refluxed for 17 hours, cooled and thealcohol evaporated off. The residue is extracted with ether after makingit alkaline with 40 percent sodium hydroxide. The ether is dried overpotassium carbonate and evaporated. The residue is dissolved inmethanol, the pH adjusted to about 7, charcoal filtered and evaporated.The residue is triturated with ether and the solid that forms isrecrystallized from water to obtain 1-(2,4,6-trichlorophenyl) biguanidehydrochloride (m.p. l70-l72 C).

Example 7 l-[3,5-Di(trifluoromethyl1biguanide to 22.9 g (0.1 mole) of3,5-di(trifluoromethyl)aniline and 8.4 g (0.1 mole) of cyanoguanidine isadded 10 ml of concentrated hydrochloric acid and 20 ml of water. Thesolution is heated on a steam bath for 1 hour at which time a solidprecipitates out. The reaction mixture is cooled to room temperature,made strongly alkaline with 40 percent NaOH and extracted with ether.The ether layer is dried over potassium carbonate, and evaporated invacuo to obtain an oil. The residue is triturated with 500 ml heptaneand the solid which forms is recrystallized from methylene chloride toobtain 1- l3,5-di(trifluoromethyl)phenyl] biguanide. (m.p. l48l49C).

Example 8 l-( 2 ,3 ,4,6-Tetrafluorophenyl )biguanide A mixture of 7.0 g(0.035 mole) of 2,3,4,6- tetrafluoroaniline hydrochloride and 2.9 g(0.035 mole) of cyanoguanidine is heated at a melt for 1 1/2 hours. Themixture is then cooled, heated with 25 ml of water until solution andthen made alkaline with 40 percent sodium hydroxide. The solution isextracted with ether and dried over potassium carbonate and evaporatedto dryness. The residue is chromatogramed on silica gel usingisopropanol:NH l-l to obtain 1- (2,3,4,6-tetrafluorophenyl)biguanide.

Example 9 When the procedures of Examples l-8 are followed but thestarting materials are substituted for those below, then thecorresponding product is obtained.

Starting Material Product 2,6-dibromoanilinel-(2,6-dibromophenyl)biguanide 2,3,4-trichloroanilinel-(2,3,4-trichlorophenyl )biguanide 2,3 ,S-trichloroaniline l-(2,3 ,5-trichlorophenyl )biguanide l-(2,6-dichloro-4- nitrophenyhbiguanidel-(2,6-dimethoxyphenyl )biguanide l-2,6-dichloro-4-(pchlorophenyl)phenylbiguanide 2,6-dichloro-4-nitroaniline 2,6-dimethoxyaniline2,6-dichloro-4-(pchlorophenyl )aniline2,6-dichloro-4-dimethylsulfamideanilinel-2,6-dichloro-4-dimethylsulfamidophenyl) biguanidel-(2,6-difluorophenyl)biguanide l-(2.6-dichlorobenzyl )biguanidel-(2,6-dibromobenzyl )biguanide l-(2,4,6-trichlorobenzyl)biguanidel-(2.fi-dichloro-a-methylbenzyl) biguanide 2,6-difluoroaniline2,6-dichlorobenzylamine 2,6-dibromobenzylamine2,4,6-trichlorobenzylamine 2,6-dichloro-a-methylbenzylamineZ,4,o-trichloro-a-methylbenzyamine l-(2,4,6-trichloro-u-methylbenl-(2,6-dinitrophenyl)biguanide 2,6-dinitroanilinc l 3,4,5-trimethoxyphenyl)bigua- 3,4,5-trimethoxyaniline 2,4,6-trimethoxyanilinel-(2,4,6-trimethoxyphenyl)biguanide l-(3 ,5 '-dichloro-4-methoxy- 3,5-dichloro-4-methoxyaniline phenyl)biguanide 2,3,4.5-tetrafluoroaniline2,6-difluorobenzylamine 2,6-dibromo-a-methylbenzylaminc2,6-dichloro-4-hydroxyaniline 2,4,6-tribromobenzylamine2,6-dichloro-4-carboxyaniline 4-phenylaniline 2,6-dicloro-4-carbethoxyaniline 2.6-dicarbethoxyaniline 4-acetoxybenzylamine mp-trilluoromethoxybenzyl-amine 4-(p-chlorophenoxy)aniline2,6-dichloro-4-dimethylamino aniline p-cyanobenzylamine 2,6-di(trifluoromethyl)aniline p-fluoro-a-methylbenzylamine2,6-dichloro-a,a-dimethylbenzyll-(2,3,4,5-tetrafluorophenyl)- biguanidel-(2,6-dibromo-a-methy benzyl)- biguanide l-(2,6-dichloro-4-hydroxyphenyUbiguanide l-(2,4,6-tribromobenzyl)biguanidel-(2,6-dichloro4-carboxyphenyl)- biguanide l-(4-biphenylyl)biguanidel-(2,6-dichloro-4-carbethoxyhenyl)bi uanide l- 2,6-dicar ethoxyphenyl)-biguanide l-(4-acetoxybenzyl)biguanide l-(o,m &

p-trifluoromethoxybenzyl) biguanide l[4-(p-chlorophenoxy)phenyl I-biguanide I 2,6-dichloro-4- dimethylaminophenyl) biguanidel-(p-cyanobenZyDbiguanide l-[2,6-di(triflyoromethyl)- henyl lbiguanidelp-fluoro-a-methylbenzynbiguanide l-(2.6-dichloro-'a,a-

dimethylbenzyl) biguanide l-(p-chloro-a-methylbenzyl)- aminep-chloro-a-methylbcnzylaminc biguanide o &

m-trifluoromethyl-a-methylbenzylamine l-(o &

m-trifluoromethyl-amethylbenzyl) biguanide l-( 2.6-di-ipropylphenyl)biguanide 2,4-dichloroaniline l 2,4-dichlorophenyl )biguanide2,4-dibromoaniline l 2.4-dibromophenyl )biguanide 2,4-difluoroanilinel-(2,4-difluorophenyhbiguanide 2,6-di-i-propylaniline2,3-difluoroaniline 2,3-difluorophenyl)biguanide 2,5-difluoroaniline2,5-difluorophenyl)biguanide The following examples are representativeof converting one substituent to another.

Example 10 l-(2,6 Dibromo-4-trifluoromethylphenyl)biguanide thecorresponding product is obtained.

Startin Material Product l-(4-tnfluoromethylphenyl) biguanidel-(2,6-dibromo-4-trifluoromethylphenyl)biguanide l-(4-bromophenyl)biguanide l-( 2,4,6-tribromophenyl )biguanide l2,6-dibromo-4- fluorophenyl )biguanide l 2,6-dibromo-4-l-(4-fluorophenyl)biguanide l'(4-chlorophenyl )biguanidechlorophenyl)biguanide l-( 2,6-dichlorophenyl)biguanidel-(2,6-dichloro-4- bromophenyl )biguanide l-( 4-iodophenyl)biguanide l-(2,6-dibromo-4 iodophenyl )biguanide l-( 2,6-dibromo-4- nitrophenyl)biguanide l-(2,6-dibromo-4 '-chloro-4- biphenyl)biguanide l-(2,6-dibromo-4-phenoxyphenyl)biguanide 1-(4-nitrophenyl)biguanide l-(4-chloro-4-biphenyl)biguanide l-(4-phenoxyphenyl)biguanide l-[4-(4-chlorophenoxy )phenyl 1- biguamde l-[ 2,6-dibromo-4-(4'-chorophenoxy )phenyl lbiguan e l-(2,4-dichloro-6- bromophenyhbiguanidel-(2,4-dichlorophenyl )biguanide When chlorine is used in the aboveexample, then the corresponding chlorinated product is obtained.

Example I l l-( 2,6-Dichloro 4-thiocyanatophenyl)biguanide A solution of1-(2,6-dichlorophenyl)biguanide (28.0g- )(0.lmole) in methanol (60 ml)previously saturated with sodium bromide is cooled to 5 C with stirring,Sodium thiocyanate is added and stirring continued for 10 minutes.

To this mixture is added dropwise with stirring, a solution of bromine(17.6 g) in methanol (20 ml) previously saturated with sodium bromide.

When reaction is complete, water is added (300 ml) and the mixture madealkaline (pHlZ) with 40 percent sodium hydroxide. The organic base isextracted into Product l -(2,6-dibromo-4-thiocyanatrophenyl )biguanidel-( 2,4-dichloro--thiocyanatophenyl)biguanidel-(2-chloro-4,G-dithiocyanato- Starting Materiall-(2,6-dibromophenyl)biguanide l-(2,4-dichlorophenyl)biguanidel-(2-chlorophenyl)biguanide phenyl)biguanidel-(2,4-dibromophenyl)biguanidel-(2,4-dibromo-fi-thiocyanatophenyl)biguanide Example 12l-(4-Nitro-2,6-dichlorophenyl)biguanide l-(2,6-Dichlorophenyl)biguanidehydrochloride (14 g) is added to concentrated sulfuric acid l 8 ml) andstirrcd for 5 minutes. Concentrated nitric acid (Sp. G. L5 1) (2.5 ml)is added dropwise, maintaining the temperature between 30 and 40 bywater cooling if necessary.

After addition of the nitric acid is complete, the mixture is stirredfor 10 minutes, then poured into water.

The mixture is made alkaline with sodium hydroxide, then extracted withether. The ether extract is washed, dried (Na SO evaporated and theresidue crystallized from aqueous methanol to give l-(4-nitro-2,6-dichlorophenyl)biguanide.

When the procedure of Example 12 is followed but the starting materialis substituted for those below, then the corresponding product isobtained.

Starting Material l-l 4-(p-chlorophenyl)phenyl biguanide Product l-(2,6-dinitro-4-trifluoromethylphenyl)biguanide l-(2,6-dinitro-4-bromophenyl)biguanide l-(2-iodo-4,6-dinitrophenyl)- biguanidel-(2,6-dinitro-4- chlorophcnyl)biguanidc l-(2,6-dinitro-4- iodophcnyl)higuunidc l-( 2,4-dichlro-6- nitrophcnylihiguunidc l-(2,4-dibromo-6-nitrophcnyhbiguanidc l-( 2-chloro-4,6-dinitrophenyl biguanide l-(2-iodo-4,6-dinitrophenyl biguanidel-[2,6-dinitro-4-(pchlorophenoxy)phenyllbiguanidel-(2,6-dichloro-4-nitro-a-methylbenzyl )biguanide l- (2,6-dibromo-4-nitrophenyhbiguanide l -]2,6-dinitro-4 -(p-cl1lorophenyl)phenyl]-biguanide Example 13 l-(2,6-Dibromophenyl)biguanide hydroiodide Asolution of l-(2,6-dibromo-4- iodophenyl)biguanide (47g) (0.1 mole) inmethanol (500 ml) is shaken in an atmosphere of hydrogen in the presenceof percent palladium or charcoal (l g). When the hydrogen uptake ismeasured to be 2.4 l. at

RT. and P., the shaking is stopped and the mixture filtered throughdiatomaceous earth.

The filtrate is evaporated to dryness and the solid residue dissolved inmethanol ml). Upon addition of ether ml) with stirring, l-(2,6-dibromophenyl)biguanide hydroiodide is obtained.

Example 14 Ten thousand tablets for oral use, each containing 50 mg ofl-(2,6-dichlorophenyl)biguanide hydrochloride, are prepared from thefollowing types and amounts of material:

lngredient Grams l-( 2,6-dichlorophenyl )biguanidc hydrochloride 500Lactose U.S.P. 350 Potato Starch U.S.P. 346

The mixture is moistened with an alcoholic solution of 20 grams ofstearic acid and granulated through a sieve. After drying, the followingingredients are added:

Ingredient Grams Potato Starch U.S.P. 320 Talcum 400 Magnesium Stearate500 Colloidal Silicium Dioxide 64 The mixture is thoroughly mixed andcompressed into tablets.

Example l5 Five hundred ampoules each with two ml of solution whichcontain 15 mg of l-(2,4,6-trichlorophenyl)- biguanide hydrochloride isprepared from the following types and amounts of materials:

Ingredient Grams l-( 2,4,6-trichlorophenyl )biguanide hydrochloride 7 .5Ascorbic acid, 1 Sodium bisulphite 0.5

Sodium sulphite l The previous ingredients are added to distilled water,diluted to 1 liter of solution and thoroughly mixed. The solution isused to fill ampoules which are sterilized hot in the usual way.

Example l6 An elixir in which each 5 ml contains 50 mg ofl-(ptrifluoromethylphenyl)biguanide hydrochloride is prepared bydiluting 750 ml of invert sugar with 100 ml of water and adding to this0.3 g of benzoic acid and 10 g of l-(p-trifluoromethylphenyl)biguanidehydrochloride. 100 ml of alcohol (U.S.P.) containing 0.2 g of flavors isadded and water is added to a total volume of 1 liter. The solution isthoroughly mixed, filtered, and bottled.

Example 17 capsule contains 500 mg of the composition and thus 150 mg ofl-(2,6-dichloro-a-methylbenzyl) biguanide hydrochloride.

Example 18 Tablets are prepared as follows:

100 g of 1-(2,6-dibromophenyl)biguanide hydrochloride,

20 g of corn starch,

14 g of calcium carbonate, and

l g of magnesium stearate.

The active compound and the starch are thoroughly mixed, moistened witha 10 percent gelatin solution, and granulated by pressing through anumber 20 sieve. The granules are dried, thoroughly mixed with calciumcarbonate and magnesium stearate, and compressed into tablets, eachweighing about 125 mg and containing 100 mg ofl-(2,6-dibromophenyl)biguanide hydrochloride.

Example [9 Composition:

75 g of l-(2,6-dichlorophenyl)biguanide hydrochloride 50 g ofmicrocrystalline cellulose,

10 g of polyvinylpyrrolidine,

g of magnesium stearate, and

85 g of starch.

The active compound and cellulose are intimately mixed, moistened with apolyvinylpyrrolidine solution in water, and granulated by pressingthrough a number sieve. The dried granules are mixed with starch andmagnesium stearate and are compressed to dragee cores, each weighing 225mg. The cores are now provided with an elastic subcoat of an aqueoussugar solution containing 60 g of powdered acacia, 60 g of powderedgelatin, and 600 g of sugar per liter of solution. Thereafter a dustingpowder mixture of 180 g of powdered sugar, 60 g of powdered starch, l gof powdered talc, and l g of powdered acacia is applied to the drageecores. Coating with the gelatin subcoat and dusting are repeated aboutfive times. The thus treated cores are sugar coated in the coating panwith a 60 percent sugar solution. Sugar coating is repeated until eachdragee weighs about 400 mg.

Example Composition:

50 g of l-(2,6-dichlorophenyl)biguanide hydrochloride,

200 g of magnesium hydroxide gel,

200 g of aluminum hydroxide gel,

240 g of sorbitol,

10 g of methyl p-hydroxybenzoate, and

q.s. 5,000 cc. of distilled water.

The ingredients are intimately dissolved and suspended in the distilledwater. Flavoring agent may be added thereto if desired. 5 cc. of theresulting suspension contain 50 mg of l-( 2 ,6-dichlorophenyl)biguanidehydrochloride, 200 mg of magnesium hydroxide, and 200 mg of aluminumhydroxide.

Example 21 i 50 g of l-(p-trifluoromethylphenyl)biguanide acetate,

5 g of propyl p-hydroxybenzoate are dissolved and diluted to 5,000 cc.with twice distilled water after the addition of modified Sorensenbuffer solution in an amount sufficient to adjust the pH- value to a pHof 6.0. Sodium chloride is dissolved therein in an amount sufficient torender the resulting solution isotonic. The final solution is passedthrough a bacteriological filter and the filtrate is autoclaved at C for15 minutes to yield a parenterally applicable solution which contains 50mg of l-(p-trifluoromethylphenyl)biguanide acetate in 5 cc.

We claim:

1. A compound of the formula NH N11 wherein R and R and chloro, bromo,or nitro and R is phenyl or halophenyl.

2. A compound according to claim 1 where:

R and R are chloro,

bromo, or nitro; and

R is p-chlorophenyl. I

3. A compound according to claim 2 where R and R are chloro, thusforming l-(2,6,4'-trichloro-4- biphenyl)biguanide.

4. A compound according to claim 2 where R and R are bromo, thus formingl-(2,6-dibromo-4-chloro- 4-biphenyl)biguanide.

5. A compound according to claim 2 where R and R are nitro, thus formingl-(2,6-dinitro-4'-chloro-4- biphenyl)biguanide.

6. A compound according to claim 1 where R, and R are chloro,

bromo, or nitro; and

R is phenyl.

7. A compound according to claim 6 where R and R are chloro, thusforming l-(2,6-dichloro-4- biphenyl)biguanide.

8. A compound according to claim 6 where R and R are bromo, thus formingl-(2,6-dibromo-4- biphenyl)biguanide.

9. A compound according to claim 6 where R and R are nitro, thus formingbiphenyl)biguanide.

l-(2,6-dinitro-4-

2. A compound according to claim 1 where: R2 and R6 are chloro, bromo,or nitro; and R4 is p-chlorophenyl.
 3. A compound according to claim 2where R2 and R6 are chloro, thus forming1-(2,6,4''-trichloro-4-biphenyl)biguanide.
 4. A compound according toclaim 2 where R2 and R6 are bromo, thus forming1-(2,6-dibromo-4''-chloro-4-biphenyl)biguanide.
 5. A compound accordingto claim 2 where R2 and R6 are nitro, thus forming1-(2,6-dinitro-4''-chloro-4-biphenyl)biguanide.
 6. A compound accordingto claim 1 where R2 and R6 are chloro, bromo, or nitro; and R4 isphenyl.
 7. A compound according to claim 6 where R2 and R6 are chloro,thus forming 1-(2,6-dichloro-4-biphenyl)biguanide.
 8. A compoundaccording to claim 6 where R2 and R6 are bromo, thus forming1-(2,6-dibromo-4-biphenyl)biguanide.
 9. A compound according to claim 6where R2 and R6 are nitro, thus forming1-(2,6-dinitro-4-biphenyl)biguanide.